The delivery of a drug to a patient with controlled release of the active ingredient has been an active area of research for decades and has been fueled by the many recent developments in polymer science. Controlled release polymer systems can be designed to provide a drug level in the optimum range over a longer period of time than other drug delivery methods, thus increasing the efficacy of the drug and minimizing problems with patient compliance.
Nanomedicine—the fusion of nanotechnology and medicine—is among the most promising approaches to address challenges associated with conventional drug delivery methods. In the past decade, drug delivery systems constructed from polymeric nanoparticles (NPs) have been the cornerstone of progress in the field of nanomedicine. Various types of polymeric materials have been studied for NP drug delivery applications.
PLGA-PEG is the most widely used polymer for making biodegradable drug delivery systems. The self-assembly of PLGA-PEG block copolymers generally yields NPs of sizes greater than 150 nm (Karnik, 2008). Although smaller particles can be synthesized, they generally suffer from low drug encapsulation and rapid drug release (Karnik, 2008). The present inventors reported that typical maximum drug loading in PLGA-PEG was found to be 7.1 wt/wt % (Verma, 2012, incorporated herein by reference in its entirely). Other PEG based polymers showed drug loading ranging from 4.3 to 11.2 wt/wt % (Shuai, 2004; He, 2010; Missirlis, 2006).
Nanoparticles have been developed as sustained release vehicles used in the administration of small molecule drugs as well as protein and peptide drugs and nucleic acids. The drugs are typically encapsulated in a polymer matrix which is biodegradable and biocompatible. As the polymer is degraded and/or as the drug diffuses out of the polymer, the drug is released into the body. Typically, polymers used in preparing these particles are polyesters such as poly(lactide-co-glycolide) (PLGA), polyglycolic acid, poly-beta-hydroxybutyrate, polyacrylic acid ester, etc. These particles can also protect the drug from degradation by the body. Furthermore, these particles can be administered using a wide variety of administration routes. Various types of materials used for synthesizing nanoparticle drug carriers have been disclosed, for example, in US. Pat. No. 2011/0300219. Amphiphilic compound assisted nanoparticles for targeted delivery have been disclosed, for example, in US. Pat. No. 2010/0203142.
Targeting controlled release polymer systems (e.g., targeted to a particular tissue or cell type or targeted to a specific diseased tissue but not normal tissue) is desirable. It can enhance the drug effect at the target site and reduce the amount of a drug present in tissues of the body that are not targeted. Therefore, with effective drug targeting, it may be possible to reduce the amount of drug administered to treat a particular disease or condition and undesirable side effects may also be reduced.
Various benefits can be obtained through delivery of therapeutic agents through a mucosal tissue. For example, mucosal delivery is generally non-invasive, thereby avoiding uncomfortable aspects of intravenous, intramuscular, or subcutaneoud delivery means. Application of a therapeutic agent to a mucosal tissue can also reduce the effect of first-pass metabolism and clearance by circulating immune cells. However, given the tendency of natural bodily fluids to clear applied therapeutic agents from the site of administration, the administration of therapeutic agents to mucosal sites, such as the eye, nose, mouth, stomach, intestine, rectum, vagina, or lungs, among others, can be problematic.
Topical administration is the most common delivery method employed for treating diseases and conditions affecting the eye, such as corneal diseases. Common topical formulations, such as eye drops or ointments, suffer from low ocular bioavailability due to rapid drainage through the naso-lacrimal duct, near constant dilution by tear turnover, and low drug permeability across the corneal epithelium. As a result, topical formulations are normally administered multiple times daily in order to achieve therapeutic efficacy, resulting in a higher potential for side effects and lower patient compliance.
Recently, formulations using NPs as drug carriers have been proposed to overcome the limitation associated with topical administration methods. NP carriers have been shown to improve drug stability in water and also prolong drug activity by releasing encapsulated compounds in a controlled manner (Ludwig, 2005; Nagarwal 2009; Liu, 2012). NPs formulated using biodegradable polymers, such as poly(lactic-co-glycolic acid) (PLGA), have been tested for ocular topical drug delivery applications (Diebold, 1990; Zimmer, 1995). Poly(ethylene glycol)-based NPs have attracted significant attention due to their ability to improve the stability of drug carrier systems in physiological environments (Bazile, 1995; Dhar, 2008; Dong, 2007; Esmaeili, 2008).
The synthesis of surface-functionalized NP drug delivery systems has been explored. In order to achieve mucoadhesion, the synthesis typically requires two-stage synthesis whereby the first stage involves the formation of NPs, while the second stage involves the conjugation of ligands on the surface of these NPs. Recently, a new technology demonstrated the formation of targeting NPs using one-step synthesis whereby the formation of the NP and the surface functionalization can be accomplished in one step (U.S. Pat. No. 8,323,698, incorporated herein by reference). This technology is particularly useful for applications where minimal targeting ligand is required, e.g. for systemic bolus injections where the number of targeting ligands on the surface must be controlled to minimize systemic immunogenicity. When nanoparticles are formed using the one-step method, targeting ligands may be detected within the core of the nanoparticles. Thus, this methodology may not be ideal where maximum targeting is desired.
The surfaces of polymeric NPs have been functionalized with molecular ligands that can selectively bind to the ocular mucosa to increase precorneal drug retention (du Toit, 2011; Khutoryanskiy, 2011; Shaikh, 2011). To date, the most widely used method to achieve mucoadhesion exploits electrostatic interactions between the negatively charged sialic acid moieties of the corneal mucin and cationic polymers such as chitosan (Sogias, 2008). However, the electrostatic interactions may be hindered by various counter ions in the tear fluid, resulting in the clearance of these NPs by tear turnover.
A number of molecular targeting groups have been suggested in the past for targeting the human mucosal lining: U.S. Pat. No. 7,803,392 B2 filed Dec. 8, 2011, entitled “pH-sensitive mucoadhesive film-forming gels and wax-film composites suitable for topical and mucosal delivery of molecules”; US Pat. 2005/0196440, filed Sep. 8, 2005, entitled “Mucoadhesive drug delivery devices and methods of making and using thereof”; US Pat. 2005/0281775, filed Dec. 22, 2005, entitled “Mucoadhesive and bioadhesive polymers”; EP 2167044 A1, filed Dec. 11, 2008, entitled “Mucoadhesive vesicles for drug delivery”; WO 2005/117844, filed Sep. 17, 2009, entitled “Mucoadhesive nanocomposite delivery system”; WO 2010/096558, filed Feb. 18, 2010, entitled “Bi-functional co-polymer use for ophthalmic and other topical and local applications”; US Pat. 2013/0034602, filed Jul. 30, 2012, entitled “Enteric-coated capsule containing cationic nanoparticles for oral insulin delivery”, EP Pat. 2510930 A1, filed Apr. 15, 2011, entitled “Nanoparticles comprising half esters of poly (methyl vinyl ether-co-maleic anhydride) and uses thereof”; U.S. Pat. No. 8,242,165 B2, filed Oct. 26, 2007, entitled “Mucoadhesive nanoparticles for cancer treatment”; EP Pat. 0516141 B1 filed May 29, 1992, entitled “Pharmaceutical controlled-release composition with bioadhesive properties”; WO 1998/030207 A1, filed Jan. 14, 1998, entitled “Chitosan-gelatin a microparticles”; EP Pat. 1652517 B1, filed Jun. 17, 2004, entitled “Hyaluronic acid nanoparticles”; U.S. Pat. No. 8,361,439 B1, filed Aug. 20, 2012, entitled “Pharmaceutical composition of nanoparticles”. However, these documents only describe mucoadhesive materials that undergo physical interaction with the mucous lining (e.g. electrostatic interaction between cationic chitosan materials with the negatively charged mucin layer). The main disadvantage of physical interaction is that it is unspecific and much weaker compared to covalent interactions.
A few studies have reported molecular targeting groups with potential to covalently bind to mucosal tissue. Phenylboronic acid (PBA), which contains a phenyl substituent and two hydroxyl groups attached to boron, has been reported to form a complex with the diol groups of sialic acid at physiological pH (Matsumoto, 2010; Matsumoto, 2010; Matsumoto, 2009). Another class of molecules that can covalently bind to the mucous membrane is polymeric thiomers (Ludwig, 2005). These thiomers are capable of forming covalent disulfide linkage with cysteine-rich subdomains of the mucous membrane (Khutoryanskiy, 2010). Typical examples of polymeric thiomers include the following conjugates: poly(acrylic acid)/cysteine (Gugg, 2004), chitosan/N-acetylcysteine (Schmitz, 2008), alginate/cysteine (Bernkop-Schnurch, 2008) chitosan/thio-glycolic acid (Sakloetsakun, 2009) and chitosan/thioethylamidine (Kafedjiiski, 2006). A recent study also suggested that polymers with acrylate end groups are also capable of binding to the thiol moieties of mucous membrane through Michael addition (Davidovich-Pinhas and Bianco-Peled 2010). The study demonstrated that the poly(ethylene glycol) diacrylate formed stable covalent linkage with thiol groups of freshly extracted porcine small intestinal mucin under physiological conditions, which was confirmed using NMR characterization.
It is desirable to provide targeted nanoparticle delivery systems for controlled delivery of a payload to a mucosal site. In particular, it is desirable to provide improved mucoadhesive delivery systems that can be retained at a mucosal site for a sufficient period of time to provide sustained release of the payload. It is particularly desirable to be able to tune such delivery systems such that the extent of targeting and adhesion can be controlled without substantially compromising the stability of the delivery system.